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Synthesis of Novel Pyrazole Derivative Containing Aryl Phenyl Ether as Potential Antifungal Agent

우수한 항균 활성을 나타내는 aryl phenyl ether pyrazole계 화합물의 합성

  • Singh, Jagdamba (Environmentally Benign Synthesis Lab, Department of Chemistry, University of Allahabad) ;
  • Verma, Pankaj Kumar (Environmentally Benign Synthesis Lab, Department of Chemistry, University of Allahabad) ;
  • Tiwari, Kamleshwar (Environmentally Benign Synthesis Lab, Department of Chemistry, University of Allahabad) ;
  • Singh, Shyam Babu (Environmentally Benign Synthesis Lab, Department of Chemistry, University of Allahabad)
  • Received : 2010.08.21
  • Accepted : 2010.11.06
  • Published : 2011.04.20

Abstract

Keywords

Pyrazole;imidazole;aryl phenyl ether;fungicides

RESULTS AND DISCUSSION

The synthesis of compound 4 (a-i) was carried out via a three step reaction which involves an N-alkylation of imidazole with the substituted bromoacetopheone 1 (a-i). This affords the corresponding 1-[4-(4-Chloro-phenoxy)-phenyl]-2-imidazol-1-yl-ethanone, 2 (a-i), in accordance with literature6 procedure. Compound 2 (a-i) on condensation with substituted benzaldehyde gave α,β-unsaturated ketones 3 (a-i). These compounds, when treated with hydrazine or substituted hydrazine, gave titled compounds 4 (a-i) (Scheme 1).

Scheme 1.

In vitro antifungal activity was measured by means of the minimal inhibitory concentrations (MIC) using the serial dilution method in 96-well micro test plates. Fungal strains used in test were obtained from the ATCC or clinical isolates. The MIC determination was performed according to the national committee for clinical laboratory standards (NCLCC) recommendations. The results of antifungal activities of the target compounds in vitro are listed in Table 1.

Table 1.Activity of compound 4 (a-i) against A. Niger and C. Albicans

The antifungal activity of compounds 4c, 4d, 4h, and 4i were remarkable reaching MIC values of 0.06 μg/mL even at 48 hrs for C. albicans. and 1.00 μg/mL even at 48 hrs for A. niger. Their activities were superior to that of the reference drug Amphotericin B and Miconazole. From the obtained data it seems that the presence of the electronwithdrawing group chloro or bromo groups at the para position in the phenyl residue enhances the activity. Moreover, synthesized compounds show better activity for C. albicans. Finally, concluded that by introduction of aryl phenyl ether group in imidazole derivatives, a new type of fungicidal candidate was synthesized and activity is enhanced.

 

EXPERIMENTAL

To a solution of 2-Bromo-1-[4-(4-chloro-phenoxy)-phenyl]-ethanone (0.1 mol) and imidazole (0.12 mol) in ethyl acetate (70 mL) was added potassium carbonate (0.12 mol), the resulting mixture was refluxed for 6 hours and the filterate was condensed. The residue was recrystallized with ethyl acetate to give compound 2.

To a solution of compound 2 (10 mmol), 80 mL of toluene, 4-substituted benzaldehyde (13 mmol) and piperidine were added. The reaction mixture was stirred under reflux for 16 hrs. The solvent was removed under reduced pressure and the residue was extracted with CHCl3 (300 mL) and the organic phase was washed with distilled water. The collected organic phase were dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was crystallised from diethyl ether.

To an ethanolic solution of compound 3 (5 mmol), hydrazine (6 mmol) or methyl hydrazine sulphate (6 mmol) was added with stirring. The reaction was allowed to stirring at room temperature and monitored by T.L.C. The solvent was evaporated under reduced pressure and solid obtained was recrystallized from diethyl ether.

4a: mp 173-175 ℃; yield 54%, 1H NMR (CDCl3, TMS): δ 3.73 (s, 3H, OCH3), 4.80 (d, 1H, CH, H5 pyrazole, JH5-H4= 6.10 Hz), 5.54 (d, 1H, CH, H4 pyrazole, JH5-H4 = 6.10Hz), 6.41 (s, broad signal, 1H, NH, disappearing on deuteration), 6.86-7.60 (m, 15H, 12H arom. and 3H imidazole). 13C NMR (CDCl3, TMS):; δ; 56.0, 70.0, 73.2, 117.4, 118.7, 126.4, 126.9, 127.2, 128.6, 129.2, 129.5, 129.7, 130.7, 131.8, 134.4, 136.8, 139.4, 145.7, 154.2.

4b: mp 177-178 ℃; yield 61%, 1H NMR (CDCl3, TMS): δ; 2.78 (d, 3H, NCH3), 4.0 (q, NHCH3), 4.80 (d, 1H, CH, H5 pyrazole, JH5-H4 = 6.10 Hz), 5.54 (d, 1H, CH, H4 pyrazole, JH5-H4 = 6.10 Hz), 6.41 (s, broad signal, 1H, NH, disappearing on deuteration), 6.86-7.60 (m, 15H, 12H arom. and 3H imidazole). 13C NMR (CDCl3, TMS): δ 35.3, 70.0, 73.2, 117.4, 118.7, 126.4, 126.9, 127.2, 128.6, 129.2, 129.5, 129.7, 130.7, 131.8, 134.4, 136.8, 139.4, 145.7, 154.2.

4c: mp 159-161 ℃; yield 59%, 1H NMR (CDCl3, TMS): δ; 4.79 (dd, 1H, CH, H5 pyrazole, JH5-H4 = 5.86 Hz; JH5-NH = 2.20 Hz), 5.54 (d, 1H, CH, H4 pyrazole, JH5-H4 = 5.86 Hz), 6.46 (d, 1H, NH, disappearing on deuteration; JNH-H5 = 2.20Hz), 6.94-7.61 (m, 15H, 12H arom. and 3H imidazole). 13C NMR (CDCl3, TMS): δ 70.0, 73.2, 116.9, 118.7, 125.8, 126.4, 126.9, 127.8, 128.6, 129.5, 129.7, 130.7, 131.8, 136.8, 139.4, 145.7, 154.2.

4d: mp 170-171 ℃; yield 49%, 1H NMR (CDCl3, TMS): δ; 4.80 (d, 1H, CH, H5 pyrazole, JH5-H4 = 6.10 Hz), 5.54 (d, 1H, CH, H4 pyrazole, JH5-H4 = 6.10 Hz), 6.41 (s, broad signal, 1H, NH, disappearing on deuteration), 6.86-7.60 (m, 15H, 12H arom. and 3H imidazole). 13C NMR (CDCl3, TMS): δ 70.0, 73.2, 117.4, 118.7, 126.4, 126.9, 127.2, 128.6, 129.2, 129.5, 129.7, 130.7, 131.8, 134.4, 136.8, 139.4, 145.7, 154.2.

4e: mp 175-177 ℃; yield 56%, 1H NMR (CDCl3, TMS): δ 2.35 (s, 3H, CH3), 4.80 (d, 1H, CH, H5 pyrazole, JH5-H4 = 6.10 Hz), 5.54 (d, 1H, CH, H4 pyrazole, JH5-H4 = 6.10 Hz), 6.41 (s, broad signal, 1H, NH, disappearing on deuteration), 6.86-7.60 (m, 15H, 12H arom. and 3H imidazole). 13C NMR (CDCl3, TMS): δ 20.0, 70.0, 73.2, 117.4, 118.7, 126.4, 126.9, 127.2, 128.6, 129.2, 129.5, 129.7, 130.7, 131.8, 134.4, 136.8, 139.4, 145.7, 154.2.

4f: mp 149-151 ℃; yield 58%, 1H NMR (CDCl3, TMS): δ 2.96 (s,3H, CH3), 3.73 (s, 3H, OCH3), 4.16 (d, 1H, CH, H5 pyrazole, JH5-H4 = 10.98Hz), 5.55 (d, 1H, CH, H4 pyrazole, JH5-H4 = 10.98Hz), 6.92-7.60 (m, 15H, 12H arom. and 3H imidazole). 13C NMR (CDCl3, TMS): δ 41.5, 56.0, 71.3, 80.7, 117.3, 118.7, 125.8, 126.3, 126.9, 127.7, 128.6, 128.7, 129.5, 130.9, 131.9, 136.7, 139.4, 145.9, 154.2.

4g: mp 143-145 ℃; yield 69%, 1H NMR (CDCl3, TMS): δ 2.78 (d, 3H, NHCH3), 2.96 (s,3H, CH3), 4.0 (q,1H, NH), 4.16 (d, 1H, CH, H5 pyrazole, JH5-H4 = 10.98Hz), 5.55 (d, 1H, CH, H4 pyrazole, JH5-H4= 10.98Hz), 6.92-7.60 (m, 15H, 12H arom. and 3H imidazole). 13C NMR (CDCl3, TMS): δ 35.3, 41.5, 71.3, 80.7, 117.3, 118.7, 125.8, 126.3, 126.9, 127.7, 128.6, 128.7, 129.5, 130.9, 131.9, 136.7, 139.4, 145.9, 154.2.

4h: mp 148-150 ℃; yield 73%, 1H NMR (CDCl3, TMS): δ 2.96 (s, 3H, CH3), 4.16 (d, 1H, CH, H5 pyrazole, JH5-H4 = 10.98 Hz), 5.55 (d, 1H, CH, H4 pyrazole, JH5-H4 = 10.98 Hz), 6.92-7.60 (m, 15H, 12H arom. and 3H imidazole). 13C NMR (CDCl3, TMS): δ 41.5, 71.3, 80.7, 117.3, 118.7, 125.8, 126.3, 126.9, 127.7, 128.6, 128.7, 129.5, 130.9, 131.9, 136.7, 139.4, 145.9, 154.2.

4i: mp 136 ℃; yield 51%, 1H NMR (CDCl3, TMS): δ 2.95 (s, 3H, CH3), 4.17 (d, 1H, CH, H5 pyrazole, JH5-H4 = 10.98 Hz), 5.54 (d, 1H, CH, H4 pyrazole, JH5-H4 = 10.98 Hz), 6.84-7.60 (m, 15H, 12H arom. and 3H imidazole). 13C NMR (CDCl3, TMS): δ 41.5, 71.6, 80.7, 117.4, 118.7, 126.4, 126.9, 127.0, 128.6, 129.3, 129.5, 129.7, 130.7, 121.9, 134.5, 136.8, 139.9, 145.8, 154.2.

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